Chitosan materials are typically produced using dilute aqueous solutions of acetic, hydrochloric, formic, glycolic, lactic, and other acids to readily dissolve and solubilize chitosan powder. Conventionally, this chitosan powder solubilized in acidic solution is then directly used to produce chitosan material finished forms, and the acids used for chitosan powder solubilization continue to reside in and be part of the chitosan material finished forms absent further processing. All acids, including, but not limited to, acetic, lactic, hydrochloric, glycolic and glutamic acid, that solubilize chitosan in aqueous solution interact with chitosan to form an acid salt complex, wherein the cation moiety of the salt complex is a positively charged glucosammonium of the chitosan and the anion counter-ion negatively charged moiety is provided from the anion of the added acid. The formation of this acid salt complex is the reason that chitosan becomes solubilized in water at about pH≤6.5. On removal of the water from the chitosan acidic solution, the salt complex substantially remains, i.e., at a presence of ≥about 5.0% w/w in the chitosan affecting its biocompatibility and its bioactivity.
Deleterious secondary or post-processing of the chitosan material finished forms is required to remove or extract the resident acid in order to achieve, among other things, non-adherent chitosan finished forms and to mitigate the adverse effects that unwanted acid presence can have on biocompatibility. See Berscht, P. C., Nies, B., Liebendorfer, A., and Kreuter, J., In Vitro evaluation of biocompatibility of different wound dressing materials, JOURNAL OF MATERIALS SCIENCE: MATERIALS IN MEDICINE, 1995, 6: p. 201-205 (“Berscht”); Johnson, R. S., Lewis, T. W., and Lampecht, E. G., In vivo tissue response to implanted chitosan glutamate, ADVANCES IN CHITIN AND CHITOSAN, C. J. Brine, P. Sandford, and J. P. Zikakis, Editors. 1992, Elsevier: Amsterdam. p. 3-8 (“Johnson”); Cafaggi, S., Leardi, R., Parodi, B., Caviglioli, G., Russo, E., and Bignardi, G., Preparation and evaluation of a chitosan salt-poloxamer 407 based matrix for buccal drug delivery, JOURNAL OF CONTROLLED RELEASE, 2005. 102(1): p. 159-169 (“Cafaggi”); Grabovac, V., Guggi, D., and Bernkop-Schnürch, A., Comparison of the mucoadhesive properties of various polymers, ADVANCED DRUG DELIVERY REVIEWS, 2005. 57(11): p. 1713-1723 (“Grabovac”); Sigurdsson, H. H., Loftsson, T., and Lehr, C.-M., Assessment of mucoadhesion by a resonant mirror biosensor, INTERNATIONAL JOURNAL OF PHARMACEUTICS, 2006. 325(1-2): p. 75-81 (“Sigurdsson”); He, Q., Ao, Q., Gong, Y., and Zhang, X., Preparation of chitosan films using different neutralizing solutions to improve endothelial cell compatibility, JOURNAL OF MATERIALS SCIENCE: MATERIALS IN MEDICINE, 2011, 22(12): p. 2791-2802 (“He”).
Further, the acid-removal processing of conventional chitosan material finished forms involves solvent extraction or other harsh processes and undesirably and negatively alters the chitosan material finished form properties including its shape, structure, capacity for viable drug stability, retention, and delivery, porosity, morphology, and other mechanical properties. Additional post-processing acid removal steps also add further difficulty, complications, and costs to the manufacture of conventional chitosan material finished forms.
The present invention addresses a long-standing need in the art to produce chitosan material native final forms that are substantially free of acid salts upon their production, i.e., no subsequent and additional processing steps are required to remove resident acids from the chitosan material finished forms. Surprisingly, the inventors of the present invention not only found a solution to this long-standing problem, but have also discovered and developed robust and unique chitosan material native final forms that, unlike prior art chitosan material finished forms, can be applied without significant change on wetting, can remain on wounds, or treated wet tissue surfaces, wetted over four to seven days without significant change, do not dissolve in water, saline, blood or other biological fluid, can be used to readily contain active pharmaceutical ingredients, can be used to achieve controlled release of pharmaceutical ingredients, can be molded as hydrogels to designed shape, can achieve remarkable fluid absorbency while substantially retaining their overall shape dimensions, or serve as drug delivery vehicles, conform readily to surfaces, can be easily removed, and/or can be removed intact (with absence of tearing, fragmentation, or breaking into pieces).